Blocking activation of CD4−CD8− T cells modulates their cytotoxic potential and decreases the expression of inflammatory and chemotactic receptors

• Published in: Clinical immunology (Orlando, Fla.) Fla.), 2023-06, Vol.251, p.109331-109331, Article 109331
• Main Authors: Neves, Eula Graciele Amorim, Koh, Carolina Cattoni, Lucinda, Pedro Paulo Diniz, Souza-Silva, Thaiany Goulart, Medeiros, Nayara I., Pantaleão, Alexandre, Mutarelli, Antônio, Gomes, Juliana de Assis Silva, Silva, Silvana de Araújo, Gollob, Kenneth John, Nunes, Maria do Carmo Pereira, Dutra, Walderez Ornelas
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents; Cardiomyopathy; CD8-Positive T-Lymphocytes - metabolism; Chagas Cardiomyopathy; Chagas Disease; Chemokine receptors; Cytokines - metabolism; Cytotoxic molecules; DN T cells; Humans; Inflammation; Trypanosoma cruzi - metabolism
• ISSN: 1521-6616; 1521-7035
• DOI: 10.1016/j.clim.2023.109331

CD4−CD8− (double negative – DN) T cells represent a small fraction of circulating T lymphocytes but are a major source of pro-inflammatory cytokines in patients with infectious diseases, including chronic Chagas cardiomyopathy (CCC), one of the deadliest cardiopathies known. Chagas disease is caused by an infection with the protozoan parasite Trypanosoma cruzi and can lead to either an asymptomatic form or a high-mortality cardiac disease. While circulating DN T cells represent a major inflammatory cytokine-expressing cell population in Chagas disease, their potential to be recruited to the heart and to perform cytotoxicity has not been determined. Our previous studies showed that blocking DN T cell activation decreases the expression of IFN-gamma, a cytokine involved in the severity of CCC. Here, studying a well-characterized cohort of Chagas patients with CCC or the asymptomatic form of Chagas disease (indeterminate form, IND), we evaluated the expression of cytotoxic molecules, cytokine and chemokine receptors in γδ+ and αβ+ DN T cells by multiparameter flow cytometry, and investigated whether blocking the activation of DN T cells influences the expression of these molecules. We observed that DN T cells from CCC display a higher expression of granzyme A, perforin, inflammatory molecules, and inflammatory chemokine receptors than cells from IND. Messenger RNA coding for these molecules is also upregulated in the heart of CCC patients. Importantly, blocking the activation of DN T cells from CCC modulates their cytotoxic potential and the expression of inflammatory and of chemokine receptors, suggesting that targeting DN T cell activation may be a valid strategy to reduce recruitment to the heart, inflammation, cytotoxicity and, thereby diminish CCC progression and severity. [Display omitted] •DN T cells have high expression of cytotoxic markers in patients with cardiomyopathy.•DN T cells from patients with cardiomyopathy display an inflammatory profile.•DN T cells from patients with cardiomyopathy express chemotactic receptors.•Blocking CD4-CD8- T cell activation reduces their inflammatory phenotype.